Macrophage Plasticity in Health and Disease: From Homeostasis to Pathogenesis

Macrophages are ubiquitous innate immune cells that are derived from embryonic progenitors or circulating monocytes and populate all tissues. In a physiological state, tissue-resident macrophages execute immune surveillance, debris clearance, and metabolic regulation, and their numbers are also maintained by monocyte-derived macrophages. Following injury or infection, recruited monocyte-derived along with tissue-resident macrophages, undergo coordinated functional transitions to drive inflammation, tissue repair, or fibrosis. The M1/M2 macrophage nomenclature, largely derived from in vitro systems, does not fully recapitulate the complexity of tissue microenvironment, which is shaped by multiple concurrent stimuli. Despite its limitations, it remains a useful framework for describing pro- and anti-inflammatory extremes of macrophage polarization. Emerging evidence highlights the importance of mitochondria-mediated metabolic reprogramming and epigenetic regulation as central determinants of macrophage fate and function. Advances in single-cell and spatial technologies have revealed extensive macrophage heterogeneity across organs, underscoring the need to redefine macrophage biology beyond simplistic activation paradigms. The goal of this Research Topic is to dissect the molecular, cellular, and environmental mechanisms that govern macrophage plasticity across physiological and pathological states. While macrophage heterogeneity and functional adaptability are essential for effective immune defense and tissue repair, dysregulated macrophage responses can drive chronic inflammation, impaired resolution, tissue damage, and fibrosis. This topic aims to address key unanswered questions regarding how macrophage identity is shaped by tissue context, metabolic cues, mitochondrial dynamics, and inflammatory signalling, and how these processes become maladaptive during disease. Recent advances in single-cell and spatial transcriptomics, metabolic profiling, lineage tracing, and in vivo imaging have markedly expanded our ability to define macrophage diversity and fate decisions within complex tissue immune microenvironments. By integrating mechanistic and systems-level approaches across multiple organs, this Research Topic seeks to identify conserved and tissue-specific pathways that regulate macrophage transitions from homeostatic to pathogenic states. Ultimately, it aims to highlight novel therapeutic strategies that restore beneficial functions of macrophages or selectively target pathogenic macrophage subsets to improve disease outcomes.This Research Topic welcomes the submission of original research, review, mini-review, and perspective articles that provide mechanistic insight into either of the following areas:1. Macrophage ontogeny and fate mapping; tissue-specific metabolic programming of macrophages; mitochondrial dynamics in modulating macrophage functions; epigenetic and transcriptional control of macrophage states.2. Macrophage interactions with tissue-resident cells across organ systems under homeostatic and pathological conditions.3. Macrophage-driven mechanisms underlying inflammation, tissue repair, fibrosis, infection, and cancer.4. Studies employing advanced approaches such as single-cell or spatial omics, computational modeling, in vivo genetic models, and translational human studies are strongly encouraged. 5. Submissions that bridge fundamental mechanisms with disease relevance and therapeutic targeting of macrophage plasticity are particularly welcomed. Topic editors: Divya Bhatia, Ambak Kumar Rai, Ramalingam Bethunaickan Source: https://www.frontiersin.org/research-topics/77519/macrophage-plasticity-in-health-and-disease-from-homeostasis-to-pathogenesis